The chemical and medical literature describes compounds that are said to be antimicrobial, i.e., capable of destroying or suppressing the growth or reproduction of microorganisms, such as bacteria. For example, such antibacterial agents are described in Antibiotics, Chemotherapeutics, and Antibacterial Agents for Disease Control (M. Greyson, editor, 1982), E. Gale et al., The Molecular Basis of Antibiotic Action 2d edition (1981), Recent Research Developments in Antimicrobial Agents & Chemotherapy (S. G. Pandalai, Editor, 2001), Quinolone Antimicrobial Agents (John S Wolfson., David C Hooper, Editors, 1989), and F. O'Grady, H. P. Lambert, R. G. Finch, D. Greenwood, Martin Dedicoat, “Antibiotic and Chemotherapy, 7th edn.” (1997).
The mechanisms of action of these antibacterial agents vary. However, they are generally believed to function in one or more ways: by inhibiting cell wall synthesis or repair; by altering cell wall permeability; by inhibiting protein synthesis; or by inhibiting the synthesis of nucleic acids. For example, beta-lactam antibacterial agents act through inhibiting essential penicillin binding proteins (PBPs) in bacteria, which are responsible for cell wall synthesis. As another example, quinolones act, at least in part by inhibiting synthesis of DNA, thus preventing the cell from replicating.
The pharmacological characteristics of antimicrobial agents, and their suitability for any given clinical use, vary. For example, the classes of antimicrobial agents (and members within a class) may vary in 1) their relative efficacy against different types of microorganisms, 2) their susceptibility to development of microbial resistance and 3) their pharmacological characteristics such as their bioavailability and biodistribution. Accordingly, selection of an appropriate antimicrobial agent in a given clinical situation requires analysis of many factors, including the type of organism involved, the desired method of administration, the location of the infection to be treated and other considerations.
However, many such attempts to produce improved antimicrobial agents yield equivocal results. Indeed, few antimicrobial agents are produced that are truly clinically acceptable in terms of their spectrum of antimicrobial activity, avoidance of microbial resistance, and pharmacology. Thus there is a continuing need for broad-spectrum antimicrobial agents, which are effective against resistant microbes.
Some 1,4-dihydroquinolone, naphthyridine or related heterocyclic moieties are known in the art to have antimicrobial activity and are described in the following references: R. Albrecht Prog. Drug Research, Vol. 21, p. 9 (1977); J. Wolfson et al., “The Fluoroquinolones: Structures, Mechanisms of Action and Resistance, and Spectra of Activity In Vitro”, Antimicrob. Agents and Chemother., Vol. 28, p. 581 (1985); G. Klopman et al. Antimicrob. Agents and Chemother., Vol. 31, p. 1831 (1987); M. P. Wentland et al., Ann. Rep. Med. Chem., Vol. 20, p. 145 (1986); J. B. Cornett et al., Ann. Rep. Med. Chem., Vol. 21, p. 139 (1986); P. B. Fernandes et al. Ann. Rep. Med. Chem., Vol. 22, p. 117 (1987); A. Koga, et al. “Structure-Activity Relationships of Antibacterial 6,7- and 7,8-Disubstituted 1-alkyl-1,4-dihydro-4-oxoquinoline-3-carboxylic Acids” J. Med. Chem. Vol. 23, pp. 1358-1363 (1980); J. M. Domagala et al., J. Med. Chem. Vol. 31, p. 991 (1988); T. Rosen et al., J. Med. Chem. Vol. 31, p. 1598 (1988); B. Ledoussal et al., “Non 6-Fluoro Substituted Quinolone Antibacterials: Structure and Activity”, J. Med. Chem. Vol. 35, p. 198-200 (1992); U.S. Pat. No. 6,329,391; A. M Emmerson et al., “The quinolones: Decades of development and use”, J. Antimicrob. Chemother., Vol 51, pp 13-20 (2003); J. Ruiz, “Mechanisms of resistance to quinolones: target alterations, decreased accumulation and DNA gyrase protection” J. Antimicrob. Chemother. Vol. 51, pp 1109-1117 (2003); Y. Kuramoto et al., “A Novel Antibacterial 8-Chloroquinolone with a Distorted Orientation of the N1-(5-Amino-2,4-difluorophenyl) Group” J. Med. Chem. Vol. 46, pp 1905-1917 (2003); Japanese Patent Publication 06263754; European Patent Publication 487030; International Patent Publication WO0248138; International Patent Publication WO9914214; U.S. Patent Publication 2002/0049192; International Patent Publication WO02085886; European Patent Publication 572259; International Patent Publication WO0136408; U.S. Pat. No. 5,677,456; European Patent Publication 362759; U.S. Pat. Nos. 5,688,791; 4,894,458; European Patent Publication 677522; U.S. Pat. Nos. 4,822,801; 5,256,662; 5,017,581; European Patent Publication 304087; International Patent Publication WO0136408; International Patent Publication WO02085886; Japanese Patent Publication 01090184; International Patent Publication WO9209579; International Patent Publication WO0185728; European Patent Publication 343524; Japanese Patent Publication 10130241; European Patent Publication 413455; International Patent Publication WO0209758; International Patent Publication WO0350107; International Patent Publication WO9415933; International Patent Publication WO9222550; Japanese Patent Publication 07300472; International Patent Publication WO0314108; International Patent Publication W00071541; International Patent Publication WO0031062; and U.S. Pat. No. 5,869,670.
WO03050107 describes a series of dihydroquinolone, naphthyridine and related heterocyclic antibacterial agents. Of particular interest is the disclosure of compounds of the formula,
wherein R8 and R8′ are hydrogen, alkyl, substituted alkyl, alkylamino, or arylalkyl, R9 is hydrogen, alkyl, alkylamino, dialkylamino, aryl, arylalkyl, or trihaloalkyl, and X is hydroxy, alkoxy, acyloxy, amino or substituted amino.
European Patent Publication 362759 discloses 1,4-dihydroquinolone and naphthyridine antibacterial agents of the formula,
wherein W is C1-3 alkylidene and R5 and R6 are hydrogen or alkyl.
International Patent Publication WO 99/14214 and U.S. Pat. No. 6,329,391 disclose-quinolone antibacterial agents-with C7-piperdinyl, C7-azetidinyl, or C7-pyrrolidinyl substituents of the formula,
Of particular interest are those compounds wherein R7 is amino, aminoalkyl, or substituted aminoalkyl and R9 is selected from hydrogen, C1-C4 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or a C3-C6 fused or spirocyclic alkyl ring. For compounds with a substituted piperidine at the 7-position of the quinolonecarboxylic acid, among the preferred substituents are 3-amino-4-methyl, 3-amino-4,4-dimethyl, 3-amino-4-spirocyclopropyl, 3-amino-6-cyclopropyl, 3-aminomethyl, 4-aminomethyl and 3-methylamino. For compounds with a substituted pyrrolidine at the 7-position of the quinolonecarboxylic acid nucleus, preferred substituents include 3-(1-aminoethyl), 3-aminomethyl, 4-(1-aminoethyl)-2,2-dimethyl, and 2-aminomethyl. For compounds with an azetidine substituent at the 7-position of the quinolonecarboxylic acid, the compounds having the substituents, 3-amino, 3-aminomethyl and 3-(1-amino-1-methyl)ethyl, are included among the preferred examples.
European Patent Publication 241206A2 discloses compounds of the formula,
wherein B is —CH2—, —(CH2)2—, or —(CH2)3—, R4 is hydrogen, C1-C3 alkyl, hydroxy, or C1-C3 alkoxy, W is hydroxy, C1-C3 alkoxy, or a group of the formula R5R6N—(CH2)n— in which n is 0 or 1 and R5 and R6 are the same or different and each represents a hydrogen atom, a C1-C3 alkyl group or an arylalkyl group, and m is 1 or 2. each symbol is as defined in the specification of the above mention publication. For the piperidine substituent at the 7-position of the quinolonecarboxylic acid, the compounds having substituents of 4-amino-3-methyl, 4-methylamino-3-methyl, 4-hydroxy-3methyl are included in the preferred examples therein.
European Patent Publication 0394553B1 discloses anti-viral compounds of the formula,
wherein R21, R22 and R23 are each independently is a hydrogen atom, a halogen atom, amino, C1-C6 alkyl, C1-C8 alkoxy, or amino C1-C8 alkyl and two of them may be combined with each other to form a Spiro ring, and n is 1 or 2.
European Patent Publication 0572259A1 discloses anti-viral compounds of the formula,
wherein R6 and R7 may be the same or different and each represents a hydrogen atom or a lower alkyl group, m is 0 or 1, n′ is 1 or 2, n″ is 1, 2, 3 or 4, and R8 is a hydrogen-atom, a lower alkyl group, a hydroxy group or a lower alkoxy group.
International Patent Publication WO9324479 discloses compounds of the formula,
wherein Z is an amino radical, R1 is hydrogen, an (optionally hydroxylated lower alkyl) radical, an acyl radical derived from a carboxylic acid, an alkyl carbonic acid or an arylsulfonic acid or an arylamino carbonyl radical, R2 is an oxygen atom, and n is 0 or 1.
Examples of bacterial infections resistant to antibiotic therapy have been reported in the past; they are now a significant threat to public health in the developed world. The development of microbial resistance (perhaps as a result of the intense use of antibacterial agents over extended periods of time) is of increasing concern in medical science. “Resistance” can be defined as existence of organisms, within a population of a given microbial species, that are less susceptible to the action of a given antimicrobial agent. This resistance is of particular concern in environments such as hospitals and nursing homes, where relatively high rates of infection and intense use of antibacterial agents are common. See, e.g., W. Sanders, Jr. et al., “Inducible Beta-lactamases: Clinical and Epidemiologic Implications for the Use of Newer Cephalosporins”, Review of Infectious Diseases, p. 830 (1988).
Pathogenic bacteria are known to acquire resistance via several distinct mechanisms including inactivation of the antibiotic by bacterial enzymes (e.g., β-lactamases hydrolyzing penicillin and cephalosporins); removal of the antibiotic using efflux pumps; modification of the target of the antibiotic via mutation and genetic recombination (e.g., penicillin-resistance in Neiserria gonorrhoeae); and acquisition of a readily transferable gene from an external source to create a resistant target (e.g., methicillin-resistance in Staphylococcus aureus). There are certain Gram-positive pathogens, such as vancomycin-resistant Enterococcus faecium, which are resistant to virtually all commercially available antibiotics.
Hence existing antibacterial agents have limited capacity in overcoming the threat of resistance. Thus it would be advantageous to provide new antibacterial agents that can be used against resistant microbes.